Immature T cell lymphomas comprise a significant portion of human lymphoid malignancies. Many of these tumors harbor recurrent chromosomal translocations and related aberrations that either activate proto-oncogenes, inactivate tumor suppressor genes, or create novel oncogenic fusion genes. Most oncogenic translocations of human immature T cell lymphomas are thought to occur via errors in the repair of DNA double strand breaks (DSBs) introduced at T cell receptor (TCR) loci during V(D)J recombination and/or general DSBs at other genomic locations. We propose to elucidate functions of the DSB response in suppression of translocations associated with T cell lymphomas and to generate novel mouse models for human T cell lymphoma. We also propose to elucidate molecular mechanisms that underlie recurrent translocations in T cell lymphomas, including how spatial proximity, DSB frequency and DNA repair pathway availability affect translocation patterns. Recurrent chromosome 14 translocations in the vicinity of the TCRa/d locus are found frequently in ATM-deficient mouse thymic lymphomas and similar translocations are found in human T cell lymphomas that have mutated ATM genes. In this regard, we find that a region 10 Mb upstream of the TCRa/d locus is highly amplified on chromosome 14 in most ATM-deficient mouse thymic lymphomas. We propose to fully investigate this recurrent translocation/amplification in ATM-deficient T cell lymphomas i) to elucidate mechanistic aspects, including potential roles of TCRa/d locus V(D)J recombination and TCRa/d enhancers (with Project 2, Harald von Boehmer), ii) to identify target oncogene(s) (with Project 5, Rick Young), and iii) to determine relevance to human T cell lymphomas (with Project 1 Tom Look). For translocations, participating loci on different chromosomes must be broken and must be in close proximity for joining. Thus we propose to test the hypothesis that frequent activation of certain proto-oncogenes via translocation to TCR loci in human, but not mouse, T cell lymphomas may reflect the relative frequency of DNA DSBs and the spatial proximity of target loci. To address this question, we will employ various approaches including 3D FISH and the generation of novel cell culture and mouse models in which DNA breaks are introduced into target T-cell oncogenes during T-cell development. We will also employ these models to test our hypothesis that ATM and its substrates (e.g., H2AX) prevent translocations resulting from aberrant V(D)J recombination by stabilizing TCR locus DSBs introduced during V(D)J recombination. Together, these studies should allow us to address long-standing questions regarding the mechanisms underlying chromosomal translocation targeting in T-ALL and other cancers.
Immature human T cell lymphomas often harbor recurrent chromosomal translocations that activate oncogenes or inactivate tumor suppressor genes. We propose to elucidate mechanisms of oncogenic translocations and molecular pathways that lead to thymic malignancies in mice and humans. Better understanding of fundamental processes that lead to thymic lymphoma, along with the novel mouse models we will generate via our proposed studies, should facilitate development of better treatments. Frequent interaction with investigators in this program will greatly enhance the accomplishment of our goals.
|Frock, Richard L; Hu, Jiazhi; Meyers, Robin M et al. (2015) Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 33:179-86|
|Tepsuporn, Suprawee; Hu, Jiazhi; Gostissa, Monica et al. (2014) Mechanisms that can promote peripheral B-cell lymphoma in ATM-deficient mice. Cancer Immunol Res 2:857-66|
|Anderson, N M; Harrold, I; Mansour, M R et al. (2014) BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. Leukemia 28:1145-8|
|Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-20|
|Hu, Jiazhi; Tepsuporn, Suprawee; Meyers, Robin M et al. (2014) Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes. Proc Natl Acad Sci U S A 111:10269-74|
|Anders, Lars; Guenther, Matthew G; Qi, Jun et al. (2014) Genome-wide localization of small molecules. Nat Biotechnol 32:92-6|
|Gutierrez, Alejandro; Pan, Li; Groen, Richard W J et al. (2014) Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J Clin Invest 124:644-55|
|Mansour, Marc R; Abraham, Brian J; Anders, Lars et al. (2014) Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346:1373-7|
|Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E et al. (2014) An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 46:364-70|
|Gostissa, Monica; Schwer, Bjoern; Chang, Amelia et al. (2014) IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances. Proc Natl Acad Sci U S A 111:2644-9|
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